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O6-Methylguanine-DNA Methyltransferase in Tumors and Cells of the Oligodendrocyte Lineage

Published online by Cambridge University Press:  18 September 2015

Catherine L. Nutt ,
Joseph F. Costello ,
Linda L. Bambrick ,
Daniel B. Yarosh ,
Lode J. Swinnen ,
Ann F. Chambers  and
J. Gregory Cairncross
Catherine L. Nutt
Affiliation:
Department of Pathology, University of Western Ontario London Regional Cancer Centre, London, Ontario N6A 4L6
Joseph F. Costello
Affiliation:
Neuroscience Program, Loyola University Medical Center, Maywood, Illinois
Linda L. Bambrick
Affiliation:
Department of Clinical Neurological Sciences, University of Western Ontario
Daniel B. Yarosh
Affiliation:
Applied Genetics Incorporated, Freeport, New York
Lode J. Swinnen
Affiliation:
Department of Medicine, Loyola University Medical Center, Maywood, Illinois
Ann F. Chambers
Affiliation:
Department of Oncology, University of Western Ontario Department of Pathology, University of Western Ontario London Regional Cancer Centre, London, Ontario N6A 4L6
J. Gregory Cairncross*
Affiliation:
Department of Oncology, University of Western Ontario Department of Clinical Neurological Sciences, University of Western Ontario London Regional Cancer Centre, London, Ontario N6A 4L6
*
London Regional Cancer Centre. 790 Commissioners Road. East, London. Ontario. Canada N6A 4L6
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Abstract

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Background:

Oligodendrogliomas respond to nitrosourea-based chemotherapy and are induced in rats following transplacental exposure to ethylnitrosourea, observations suggesting that neoplastic and normal cells of the oligodendrocyte lineage are “sensitive” to nitrosoureas. Nitrosoureas alkylate DNA at O6-guanine with repair mediated by O6-methyIguanine-DNA methyltransferase (MGMT). The cytotoxic and carcinogenic properties of the nitrosoureas appear related to MGMT activity.

Methods:

To explore why oligodendrogliomas respond to chemotherapy, we measured MGMT activity in five chemosensitive human oligodendrogliomas and in rat oligodendrocyte lineage cells. We also measured MGMT activity in rat astrocytes and compared the cytotoxic effects of carmustine (BCNU) on oligodendrocyte lineage cells and astrocytes.

Results:

Low levels of MGMT activity were found in five of five human oligodendrogliomas. Cultures of neonatal rat glia enriched for oligodendrocyte lineage cells also had low levels of MGMT activity, approximately one-third that found in astrocytes (p < 0.02), and oligodendrocyte lineage cells were more sensitive to BCNU than astrocytes.

Conclusions:

Low MGMT activity may contribute to the chemosensitivity of some human oligodendrogliomas and rat oligodendrocyte lineage cells also have low levels. If drug resistance mechanisms in tumors reflect the biochemical properties of their cells of origin, then normal glia may serve as a laboratory substitute for human glioma.

Type
Original Articles
Information
Canadian Journal of Neurological Sciences , Volume 22 , Issue 2 , May 1995 , pp. 111 - 115
Copyright
Copyright © Canadian Neurological Sciences Federation 1995

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